The stomach acts as the primary site of digestion of food taken into the body. The ability of the stomach to digest this food is linked to having sufficient substrates for controlled acid secretion, and functional transport proteins at the apical and basolateral membrane of the gastric gland along with sufficient bicarbonate containing mucus at the surface of the stomach to prevent erosion of the membranes due to the released acid. The regulated release of ions is normally controlled by neuronal and hormonal regulatory pathways. However, the exact mechanisms of controlled acid release are not known, as well as a complete characterization of the transport proteins that line the basolateral and apical membranes. The recent discovery of a divalent cation receptor on the basolateral membrane of the gastric gland as well as the identification of an apical Na-H transport protein and a surface cell NBC protein complex have added addition insights into the regulation of acid secretion. The ability to use an intact surface preparation, in combination with the isolated perfused single gastric gland gives important vehicles for studying and modeling the intact tissues. The regulation of these transporters and the transfer of signal information from one cell to the other is of great importance in understanding the complex issues of acid secretion in health and disease. To add to the investigative arsenal we have recently developed transgenic models that will allow direct manipulation of the secretory and regulatory pathways associated with acid secretion in the stomach. The goal of the present application is to classify, and characterize the apical and basolateral membrane associated acid-base transporters and to determine what role the newly identified divalent cation receptor plays in controlling their activity. Special emphasis will be given to the newly identified apical Na-H, and the basolateral Na/HCO3 in the gland and surface cell preparations. Additional studies will also address the role of gap junctions in regulated acid secretion. These studies will include the use of isolated perfused gastric glands, surface cells, and transgenic models to study in detail the importance of the proteins which control acid secretion. The characterization and modulation of transport proteins and receptors will enhance our basic understanding of regulated acid secretion and will play an important role in developing new strategies for the treatment of gastric related illness in the population.